Abstract
To investigate the role of liver X receptor (LXR) in adipose tissue metabolism during obesity, ob/ob mice were treated for 5 weeks with the synthetic LXR agonist GW3965. MRI analysis revealed that pharmacological activation of LXR modified fat distribution by decreasing visceral (VS) fat and inversely increasing subcutaneous (SC) fat storage without affecting whole body fat content. This was concordant with opposite regulation by GW3965 of the lipolytic markers hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) in the two fat depots; moreover, the expression of genes involved in lipogenesis was significantly induced in SC fat. Lipidomic analysis suggested that changes in lipid composition in response to GW3965 also varied between VS and SC fat. In both depots, the observed alteration in lipid composition indicated an overall change toward less lipotoxic lipids. Flow cytometry analysis showed decreased immune cell infiltration in adipose tissue of ob/ob mice in response to GW3965 treatment, which in VS fat mainly affected the macrophage population and in SC fat the lymphocyte population. In line with this, the expression and secretion of proinflammatory markers was decreased in both fat deposits with GW3965 treatment.
Highlights
To investigate the role of liver X receptor (LXR) in adipose tissue metabolism during obesity, ob/ob mice were treated for 5 weeks with the synthetic liver X receptors (LXRs) agonist GW3965
Long-term pharmacological activation of LXR in the ob/ob mouse did not impact total body fat content; it did change the ratio between VS and SC fat
While VS fat storage was reduced, SC fat storage was increased. These effects were associated with opposite changes of the lipolytic markers adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), suggesting a differential regulatory effect of LXR on lipid catabolism in VS and SC fat
Summary
Animals and experimental design Four- to five-week-old ob/ob female mice (B6.V-Lepob/J, stock no.000632, the Jackson Laboratory) were maintained in a 12 h light-dark cycle (21°C) with free access to water and chow diet (R34, Lantmännen Lantbruk). (treated) or vehicle (control) in the drinking water for 5 weeks; the concentration of vehicle components in the water was 0.5% hydroxypropyl methyl cellulose, 0.1% Tween 80, 3.6 g/l NaH2PO4, and 5.5 g/l NaHPO4. Food and drink intake was measured three times a week over a period of 3 weeks in the middle of the treatment. Two independent experiments were carried out with 7–10 animals per group. At the end of the experiments, mice were sacrificed under 4% isoflurane after 2 h of food deprivation, and blood was collected by heart puncture.
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